Human respiratory syncytial virus (RSV) RSV is the leading viral cause of lower respiratory illness and hospitalization in young children. The vast majority of children infected with RSV suffer from a mild upper respiratory tract infection; however, a small subset experience severe RSV-induced lower respiratory infection (LRI) and bronchiolitis that often requires hospitalization and can be life-threatening (Collins et al., “Respiratory syncytial virus,” In: Fields Virology, Knipe and Howley (eds.), Lippincott, Williams & Wilkins, New York (1996), pp. 1313-1351). Since nearly every child eventually is infected with RSV, and significant LRI develops in 20-30% of RSV-infected children, RSV causes more than 130,000 pediatric hospitalizations annually in the United States (Shay et al., JAMA, 282(15): 1440-1446 (1999), and World Health Organization, Initiative for Vaccine Research (IVR), Respiratory Syncytial Virus (RSV) at who.int/vaccine_research/diseases/ari/en/index3.html (2007)).
Some risk factors for the development of severe RSV-induced illness have been clearly identified, including premature birth (Navas et al., J. Pediatr., 121(3): 348-54 (1992)), bronchopulmonary dysplasia (Groothuis et al., Pediatrics, 82(2): 199-203 (1988)), congenital heart disease (MacDonald et al., N. Engl. J. Med., 307(7): 397-400 (1982)), and T cell immune deficiency (McIntosh et al., J. Pediatr., 82(4): 578-90 (1973)). However, more than half of the children hospitalized with severe RSV-induced illness do not have an identified risk factor (Boyce et al., J. Pediatr., 137(6): 865-70 (2000)), which means that approximately 1-2% of otherwise healthy children without any identifiable risk factors suffer the potentially life-threatening consequences of RSV-induced illness (Collins et al., supra).
RSV-induced severe illness in children also has been correlated with the development of asthma (see, e.g., Sigurs et al., Pediatrics, 95(4): 500-505 (1995); Welliver et al., Pediatr. Pulmonol., 15(1): 19-27 (1993); Cifuentes et al., Pediatr. Pulmonol., 36(4): 316-321 (2003); Schauer et al., Eur. Respir. 1, 20(5): 1277-1283 (2002); Sigurs et al., Am. J. Respir. Crit. Care Med., 161(5): 1501-1507 (2000); and Stein et al., Lancet, 354(9178): 541-545 (1999)). The basis for this association is unknown, but may be due to underlying genetic factors, immune dysfunction, antigen-specific responses, or structural lesions caused by lung remodeling after severe RSV disease.
Although RSV infection is almost universal by age three, reinfection occurs throughout life because natural RSV infection does not provide complete immunity (Hall et al., J. Infect. Dis., 163(4): 693-698 (1991); and Muelenaer et al., J. Infect. Dis., 164(1): 15-21 (1991)). In the elderly, RSV is an important cause of morbidity and mortality. In a retrospective cohort study, RSV was responsible for an annual average of 15 hospitalizations and 17 deaths per 1,000 nursing home residents, whereas influenza accounted for an average of 28 hospitalizations and 15 deaths in the same setting (Garofalo et al., Pediatr. Allergy Immunol., 5(2): 111-117 (1994)). Thus, RSV was isolated as frequently as influenza A in this population and was associated with comparable mortality as influenza A (Ellis et al., J. Am. Geriatr. Soc., 51(6): 761-72003; and Falsey et al., J. Infect. Dis., 172(2): 389-394 (1995)).
Currently there are no FDA-approved vaccines for the prevention of RSV infection or treatment of RSV-induced disease. The only FDA-approved medication for prophylaxis of RSV infection is SYNAGIS™ palivizumab (Medlmmune, Gaithersburg, Md.), which is a humanized monoclonal antibody directed to an epitope in the A antigenic site of the RSV F protein administered to high-risk infants. Although SYNAGIS™ palivizumab represents a significant advance in the prevention of lower respiratory tract acute RSV disease and mitigation of lower respiratory tract infection, it has not been shown to be effective against RSV infection in the upper respiratory tract at permissible doses.
RSV vaccine development has suffered from a legacy of vaccine-enhanced disease in children after natural RSV infection (Kim et al., Am. J. Epidemiol., 89(4): 422-434 (1969); and Kapikian et al., Am. J. Epidemiol., 89(4): 405-421 (1969)). For example, a formalin-inactivated alum-precipitated vaccine candidate (FI-RSV) was administered to RSV-naïve infants in the early 1960s, and although immunogenic, it did not protect the children against natural infection. In addition, vaccinees subsequently infected with RSV had increased hospitalization rates and more severe illness, including two deaths, relative to control children immunized with formalin-inactivated parainfluenza virus (Kapikian et al., supra; Chin et al., Am. J. Epidemiol., 89(4): 449-463 (1969); and Polack et al., J. Exp. Med., 196(6): 859-65 (2002)). Other approaches to RSV immunization have included live attenuated RSV, RSV subunit proteins, and parainfluenza virus chimeras. Live attenuated RSV vaccines have been tested in clinical trials of RSV-naïve infants, but have not been shown to achieve genetic stability of mutations or an optimal balance between attenuation for safety in infants and a protective immune response (Karron et al., J. Infect. Dis., 191(7): 1093-1104 (2005); and Bukreyev et al., J. Virol., 79(15): 9515-9526 (2005)). A live attenuated parainfluenza-RSV chimera vaccine containing the attachment (G) proteins of RSV types A and B has been administered intranasally and is expected to replicate safely in children (Tang et al., J. Virol., 78(20): 11198-11207 (2004); and Schmidt et al., J. Virol., 76(3): 1089-1099 (2002)). However, data from clinical testing is not yet available. Protein subunit vaccines based on RSV G and F proteins have been safely administered to adults and RSV-seropositive children, but are modestly immunogenic (Tristram et al., Vaccine, 12(6): 551-556 (1994)). In this respect, purified subunit vaccines have not induced CD8+ T-cells and have been associated with IL-4 production, thereby raising safety concerns for use in seronegative infants. Adjuvanting subunit protein vaccines with aluminum hydroxide, MPL, or a combination of MPL and QS21 did not prevent the IL-4 response (Murphy et al., Vaccine, 8(5): 497-502 (1990); and Hancock et al., J. Virol., 70(11): 7783-7791 (1996)). Subunit vaccines also have been shown to induce IgE isotype antibody (Welliver et al., J. Clin. Microbiol., 27(2): 295-299 (1989)).
Thus, there remains a need for constructs that can be used in methods to effectively prevent and/or treat RSV infection. The invention provides such constructs and methods.